Intrauterine enzyme replacement therapies for lysosomal storage disorders: Current developments and promising future prospects.

Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response. In utero enzyme replacement therapy (IUERT) is a novel approach to address these challenges evaluated in a first-in-human clinical trial for IUERT in LSDs (NCT04532047). IUERT has numerous advantages: in-utero intervention may prevent early pathology; the CNS can be accessed before the blood-brain barrier forms; and the unique fetal immune system enables exposure to new proteins with the potential to prevent an immune response and may induce sustained tolerance. However, there are challenges and limitations for any fetal procedure that involves two patients. This article reviews the current state of IUERT for LSDs, including its advantages, limitations, and potential future directions for definitive therapies.

Factors that contribute to disparities in time to acute leukemia diagnosis in young people: an in depth qualitative interview study.

BACKGROUND: Racial and ethnic disparities in outcomes for Black and Hispanic children with acute leukemia have been well documented, however little is known about the determinants of diagnostic delays in pediatric leukemia in the United States. The primary objective of this study is to identify factors contributing to delays preceding a pediatric leukemia diagnosis. METHODS: This qualitative study utilized in-depth semi-structured interviews. Parents and/or patients within two years of receiving a new acute leukemia diagnosis were asked to reflect upon their family's experiences preceding the patient's diagnosis. Subjects were purposively sampled for maximum variation in race, ethnicity, income, and language. Interviews were analyzed using inductive theory-building and the constant comparative method to understand the process of diagnosis. Chart review was conducted to complement qualitative data. RESULTS: Thirty-two interviews were conducted with a diverse population of English and Spanish speaking participants from two tertiary care pediatric cancer centers. Parents reported feeling frustrated when their intuition conflicted with providers' management decisions. Many felt laboratory testing was not performed soon enough. Additional contributors to delays included misattribution of vague symptoms to more common diagnoses, difficulties in obtaining appointments, and financial disincentives to seek urgent or emergent care. Reports of difficulty obtaining timely appointments and financial concerns were disproportionately raised among low-income Black and Hispanic participants. Comparatively, parents with prior healthcare experiences felt better able to navigate the system and advocate for additional testing at symptom onset. CONCLUSIONS: While there are disease-related factors contributing to delays in diagnosis, it is important to recognize there are multiple non-disease-related factors that also contribute to delays. Evidence-based approaches to reduce outcome disparities in pediatric cancer likely need to start in the primary care setting where timeliness of diagnosis can be addressed.

Sexual function after cervical spine surgery: Independent predictors of functional impairment.

Sexual function (SF) is an important component of patient-focused health related quality of life (HRQoL), but it has not been well studied in spine surgery. This study aims to assess SF after cervical spine surgery and identify predictors of SF. This single-center retrospective study evaluates SF of adults who underwent cervical spine surgery 2007-2012. Predictor variables included demographics, medical/surgical history, operative information, HRQoL measures (Neck Disability Index, SF-12), validated SF surveys [Female Sexual Function Index (FSFI) and Brief Sexual Function Inventory (BSFI) for males], and a study-specific SF questionnaire. 59 patients (31M, 28F; mean age=56±8.4) had significantly lower SF scores compared to age-matched peers: average BSFI = 2.26±1.22 (vs. 06±0.74), average FSFI=13.05±11.42 (<26.55 indicating sexual dysfunction). In men, lower mental SF-12 and higher NDI, back pain, and number of operated levels were associated with lower BSFI scores (all p<0.05). In women, higher total number of medications and pain medications were associated with lower FSFI scores (both p<0.05). 46% of patients reported difficulty performing a sexual position after surgery that they had previously enjoyed. 39% of men had difficulty on top during intercourse, and 32% of participants reported difficulty performing oral sex. 39% of patients reported worse SF, while only 5% reported an improvement in postoperative SF. Men and women who underwent cervical spine surgery had lower SF scores than age-matched peers, likely attributable to general mental health, regional neck disability, back pain, and medications. A large portion of patients reported subjectively worsened SF after surgery.